Frontotemporal lobar degeneration (FTLD) is a progressive neurodegenerative condition associated with focal atrophy of the frontal and/or temporal lobes. Recent exciting progress indicates that FTLD and amyotrophic lateral sclerosis (ALS) share pathogenic mechanisms. For instance, TDP-43, an evolutionarily conserved RNA- binding protein mostly localized to the nucleus, is a major pathogenic protein involved in FTLD and ALS, and in other neurodegenerative diseases. However, little is known about how TDP-43 contributes to age-dependent neurodegeneration. TDP-43 contributes to several aspects of RNA metabolism, and disease initiation or progression may involve both loss of the normal function of TDP-43 and toxic gain-of-function mechanisms. To dissect these complex mechanisms in detail, proper in vivo animal models are critically important. We propose to establish novel Drosophila models of TDP-43 toxicity and investigate how disease mutations compromise the function of TDP-43 and lead to neuronal dysfunction in vivo. These studies will likely provide important insights into the molecular pathogenic mechanisms of several neurodegenerative diseases that involve TDP- 43 pathology.